Oxygen-sensitive enzyme-prodrug gene therapy for the eradication of radiation-resistant solid tumours.

2.50
Hdl Handle:
http://hdl.handle.net/10541/84327
Title:
Oxygen-sensitive enzyme-prodrug gene therapy for the eradication of radiation-resistant solid tumours.
Authors:
Patterson, A V; Williams, Kaye J; Cowen, Rachel L; Jaffar, M; Telfer, Brian A; Saunders, Mark P; Airley, R; Honess, D; Van der Kogel, A J; Wolf, C R; Stratford, Ian J
Abstract:
Overwhelming clinical and experimental data demonstrate that tumour hypoxia is associated with aggressive disease and poor treatment outcome as hypoxic cells are refractive to radiotherapy and some forms of chemotherapy. However, hypoxia is rare in physiologically normal tissues representing a tumour-specific condition. To selectively target this therapeutically refractive cell population, we have combined bioreductive chemotherapy with hypoxia-directed gene therapy. We have transfected the human fibrosarcoma cell line, HT1080, with a hypoxia-regulated expression vector encoding the human flavoprotein cytochrome c P450 reductase (HRE-P450R). This conferred hypoxia-dependent sensitivity to the alkylating nitroimidazole prodrug RSU1069 in vitro, with a greater than 30-fold increase in oxic/hypoxic cytotoxicity ratio compared with controls. Xenografts of both the HRE-P450R and empty vector transfectants had comparable hypoxic fractions and were refractive to single dose radiotherapy of up to 15 Gy. However, combining a prodrug of RSU1069 with a reduced radiotherapy dose of 10 Gy represents a curative regimen (50% tumour-free survival; day 100) in the HRE-P450R xenografts. In complete contrast, 100% mortality was apparent by day 44 in the empty vector control xenografts treated in the same way. Thus, an oxygen-sensitive gene-directed enzyme prodrug therapy approach may have utility when incorporated into conventional radiotherapy and/or chemotherapy protocols for loco-regional disease in any tissue where hypoxia is a contra-indication to treatment success. doi:10.1038/sj.gt.3301702
Affiliation:
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK.
Citation:
Oxygen-sensitive enzyme-prodrug gene therapy for the eradication of radiation-resistant solid tumours. 2002, 9 (14):946-54 Gene Ther.
Journal:
Gene Therapy
Issue Date:
Jul-2002
URI:
http://hdl.handle.net/10541/84327
DOI:
10.1038/sj.gt.3301702
PubMed ID:
12085243
Type:
Article
Language:
en
ISSN:
0969-7128
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorPatterson, A Ven
dc.contributor.authorWilliams, Kaye Jen
dc.contributor.authorCowen, Rachel Len
dc.contributor.authorJaffar, Men
dc.contributor.authorTelfer, Brian Aen
dc.contributor.authorSaunders, Mark Pen
dc.contributor.authorAirley, Ren
dc.contributor.authorHoness, Den
dc.contributor.authorVan der Kogel, A Jen
dc.contributor.authorWolf, C Ren
dc.contributor.authorStratford, Ian Jen
dc.date.accessioned2009-10-16T12:01:28Z-
dc.date.available2009-10-16T12:01:28Z-
dc.date.issued2002-07-
dc.identifier.citationOxygen-sensitive enzyme-prodrug gene therapy for the eradication of radiation-resistant solid tumours. 2002, 9 (14):946-54 Gene Ther.en
dc.identifier.issn0969-7128-
dc.identifier.pmid12085243-
dc.identifier.doi10.1038/sj.gt.3301702-
dc.identifier.urihttp://hdl.handle.net/10541/84327-
dc.description.abstractOverwhelming clinical and experimental data demonstrate that tumour hypoxia is associated with aggressive disease and poor treatment outcome as hypoxic cells are refractive to radiotherapy and some forms of chemotherapy. However, hypoxia is rare in physiologically normal tissues representing a tumour-specific condition. To selectively target this therapeutically refractive cell population, we have combined bioreductive chemotherapy with hypoxia-directed gene therapy. We have transfected the human fibrosarcoma cell line, HT1080, with a hypoxia-regulated expression vector encoding the human flavoprotein cytochrome c P450 reductase (HRE-P450R). This conferred hypoxia-dependent sensitivity to the alkylating nitroimidazole prodrug RSU1069 in vitro, with a greater than 30-fold increase in oxic/hypoxic cytotoxicity ratio compared with controls. Xenografts of both the HRE-P450R and empty vector transfectants had comparable hypoxic fractions and were refractive to single dose radiotherapy of up to 15 Gy. However, combining a prodrug of RSU1069 with a reduced radiotherapy dose of 10 Gy represents a curative regimen (50% tumour-free survival; day 100) in the HRE-P450R xenografts. In complete contrast, 100% mortality was apparent by day 44 in the empty vector control xenografts treated in the same way. Thus, an oxygen-sensitive gene-directed enzyme prodrug therapy approach may have utility when incorporated into conventional radiotherapy and/or chemotherapy protocols for loco-regional disease in any tissue where hypoxia is a contra-indication to treatment success. doi:10.1038/sj.gt.3301702en
dc.language.isoenen
dc.subjectCancer Transplantationen
dc.subjectCulutred Tumour Cellsen
dc.subject.meshAnimals-
dc.subject.meshAnoxia-
dc.subject.meshCombined Modality Therapy-
dc.subject.meshFemale-
dc.subject.meshFibrosarcoma-
dc.subject.meshGene Therapy-
dc.subject.meshGenetic Vectors-
dc.subject.meshHumans-
dc.subject.meshMice-
dc.subject.meshMice, Nude-
dc.subject.meshMisonidazole-
dc.subject.meshNADPH-Ferrihemoprotein Reductase-
dc.subject.meshNeoplasm Transplantation-
dc.subject.meshNitroimidazoles-
dc.subject.meshProdrugs-
dc.subject.meshRadiation Tolerance-
dc.subject.meshRadiation-Sensitizing Agents-
dc.subject.meshTransplantation, Heterologous-
dc.subject.meshTumor Cells, Cultured-
dc.titleOxygen-sensitive enzyme-prodrug gene therapy for the eradication of radiation-resistant solid tumours.en
dc.typeArticleen
dc.contributor.departmentSchool of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK.en
dc.identifier.journalGene Therapyen

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